The present invention relates to antagonists of muscarinic acetylcholine receptors which are designated m-AChR. More specifically, this invention contemplates highly selective antimuscarinic agents which are characterized as esters of 3-quinuclidinol and unsymmetrical alpha-disubstituted glycolic acids.
Stimulation of the parasympathetic nervous system is achieved organically through the release of acetylcholine and may be artificially induced, for example, by certain drugs classified as parasympathomimetics. The effects of such stimulation cover a myriad of physiological responses including dilation of blood vessels, decrease in heart rate, decrease in blood pressure, stimulation of gastrointestinal smooth muscle, increase in peristalsis, stimulation of smooth muscle in the bladder causing urination, contraction of bronchial smooth muscle and constriction of the pupil. This type of stimulation also has a pronounced effect on the endocrine system causing an increase in sweating, salivation, lacrymation and pancreatic secretion. These responses are initiated at the cellular level by the interaction between the acetylcholine molecule and particular neural receptor sites.
Antimuscarinic agents, otherwise known as cholinergic blockers, are known and have been used to effect the blockade of acetylcholine transmission to the muscarine receptor site thus having the effect of anesthetising the parasympathetic nervous system. The physiological consequence is to block the stimulation or induction of the aforementioned behavorial effects.
Antimuscarinics have been employed largely in general ophthalmological procedures, e.g., for pupil dilation and during ocular surgery. These drugs are also used for anesthetic premedication in order to prohibit excessive salivary and bronchial secretions and to prevent bronchial spasms and laryngoaspasms. The antisecretory action of these drugs make them useful in treating allergic reactions such as hay fever as well.
Some of the most important aspects of antimuscarinic agents are related to gastroenterology where they are used for the treatment of spastic colon, functional diarrhea, spastic constipation, cardiospasm, and some forms of colitis and peptic ulcers. Of course, these compounds are widely employed in cardiology.
For some time, it was believed by the pharmacological and medical professions that antimuscarinics exhibited very limited selectivity, with the major differences in these drugs being quantitative rather than qualitative. Clearly, this has been a substantial disadvantage in view of the range of physiological responses for which these agents can exhibit their influence. For this reason, the use of atropine, an atropa belladonna L. alkaloid, has remained the predominant anticholinergic antispasmodic.
However, recent pharmacological studies indicate that the m-AChR exhibit subclasses, designated m.sub.1 -AChR and m.sub.2 -AChR, respectively, i.e., with selective specificity, similar to those observed with the adrenergic, dopaminergic, histaminergic and opiate receptor systems.
In accordance with the present invention new highly selective muscarinic antagonists (to m.sub.1 -AChR) have been synthesized which enable efficacy at specified sites without affecting the sites of other tissues.